Gonadotropins (or gonadotrophins) are complex glycoprotein hormones which play a central role in the regulation of reproduction in vertebrates by acting on the functions of the gonads (ovaries and testicles). Two of these hormones are secreted in all vertebrates: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In two groups of mammals, members of the horse family and primates, there is also a chorionic gonadotropin (CG) secreted by the placenta: human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG) which both act via LH receptors.
Luteinizing hormone (LH) is produced by the gonadotropic cells of the anterior lobe of the pituitary gland under stimulation from GnRH, itself produced by the hypothalamus. LH stimulates testosterone production in males, whereas it is involved in modifications of the ovarian cycle in females where it is responsible for terminal follicular growth and for ovulation and then for conversion of the ruptured ovulatory follicle into the corpus luteum. During the luteal phase of the menstrual cycle, LH stimulates progesterone secretion by the corpus luteum, essential for the early development and implantation of the embryo. LH consists of an α-subunit common to all the glycoprotein hormones of one and the same species (such as FSH, CG and thyroid-stimulating hormone, TSH), and of a β-subunit responsible for the specificity of activity of the hormone; activity which exists only if the two subunits are noncovalently linked in the form of a dimer.
Follicle-stimulating hormone (or FSH) is produced by the anterior pituitary gland under stimulation from GnRH produced by the hypothalamus. In males, it stimulates the Sertoli cells essential for spermatogenesis. In females, it is responsible for the recruitment of immature primordial follicles, for their growth and for their differentiation into pre-ovulatory follicles by stimulating the FSH receptors of the granulosa cells. FSH consists of two subunits, α and β, and has a structure similar to that of LH. Only the dimer is capable of stimulating FSH receptors.
In females, the LH and FSH levels are cyclical: very low during the period of sexual rest or outside the ovulatory period, with a secretion peak in the preovulatory period.
Gonadotropins are used in veterinary and human medicine, to induce ovulation in female mammals. Although effective, these treatments present a health risk because of the use of hormones extracted from biological fluids (blood, urine) or from tissues (pituitary glands), particularly in the veterinary field. This is the case with equine chorionic gonadotropin (eCG) extracted from gravid mare blood, and with a porcine LH and FSH extracted from pig pituitary glands. In the veterinary field, an hCG extracted from urine from pregnant women, Chorulon® (MSD laboratory) is also used.
In the human clinical field, and particularly the field of Assisted Reproductive Technology (or ART), hormones extracted from urine from menopausal women, such as Fostimon® (Laboratoire Genévrier) which is a purified FSH, and Menopur® (Ferring Pharmaceuticals laboratory), which is an hMG (human menopausal gonadotropin), a mixture of FSH and LH and the chorionic gonadotropin Endo5000, which is a purified hCG (Schering-Plough laboratory), are used. Use is also made of recombinant human FSHs, such as Gonal-F® (Merck Serono laboratory) and Puregon® (Merck Schering-Plough laboratory); and recombinant hCG and LH such as Ovidrel® and Luveris® (Merck Serono laboratory).
In addition, repeated use of these hormones usually causes an immune reaction which neutralizes the effect of the hormones, thus resulting in a decrease in therapeutic efficacy. However, it has also been demonstrated in some cases that the immune reaction can produce antibodies capable of potentiating the activity of the hormone when it is co-administered (patent EP 1 518 863) [1]. Since then, three anti-LH monoclonal antibodies capable of potentiating its action, and also that of FSH for two of them, have also been demonstrated (international application WO 2012/066519) [2].